Safety and Efficacy of Combination HDI and Anti-CTLA4 for Recurrent Inoperable Stage III or Stage IV Melanoma

• Sponsor: Ahmad Tarhini (Other)
• Overall Status: Completed
• CT.gov ID: NCT00610857
• Collaborator: Pfizer (Industry)
• Enrollment: 37
• Location: 1
• Arm: 1
• Duration (Months): 98
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

To determine the safety and efficacy of the combination of HDI and anti-CTLA-4 monoclonal antibody for patients with recurrent inoperable stage III or stage IV melanoma.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Anti-CTLA4 monoclonal antibody and HDI	Phase 2

Detailed Description

Immunity to melanoma appears to be central to disease control in the adjuvant and advanced disease settings. Spontaneous regression has been reported in melanoma, suggesting a role for host immunity, indirectly supported by the presence of lymphoid infiltrates at primary melanoma associated with tumor regression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Safety and Efficacy of Combination Biotherapy With High-dose Interferon Alfa-2b and Anti-CTLA4 Monoclonal Antibody for Recurrent Inoperable Stage III or Stage IV Melanoma
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Anti-CTLA4 monoclonal antibody and HDI Specific Aim #1: Test the hypothesis that the combination of IFNa-2b and anti-CTLA-4 monoclonal antibody will improve the response rate in patients with recurrent inoperable AJCC stage III and stage IV melanoma. Our therapeutic target is achieving, with acceptable toxicity, a 20% or better rate of objective response, CR or PR by RECIST criteria, as compared to the 5% to 10% expected in patients eligible for study. Study size is planned in terms of our primary efficacy endpoint, objective response.

Drug: Anti-CTLA4 monoclonal antibody and HDI; One course of therapy consists of three cycles (1 cycle=28days). Anti-CTLA4 monoclonal antibody (15 mg/kg i.v.) will be given during the first cycle only. HDI will be given all three cycles - cycle 1: 20 MU/m2 i.v. on days 0, 1, 2, 3, 4 a week (MTWRF) for 4 weeks; cycle 2: 10 MU/m2 s.c. 3 days a week (MWF) for 4 weeks; and cycle 3: 10 MU/m2 s.c. 3 days a week (MWF) for 4 weeks. Response assessment will be carried out at day 56 and day 84. Every patient will receive 3 cycles regardless of response status after the first 2 cycles. However, a patient may be taken off therapy in the event of clinical progression at the discretion of the treating physician. Patients without evidence for disease progression after 3 cycles may be offered additional cycles two weeks after completion of the third cycle. Therapy will continue for a maximum of 12 months.; Other Names: Anti-CTLA4 monoclonal antibody (CP-675,206)

Outcome Measures

Primary Outcome Measures

1. Best Objective Response Rate (BORR) [Up to 44 months]

   Intention to treat response rate is estimated by the proportion of patients with a best response of CR, PR, or SD by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.0

Secondary Outcome Measures

1. Progression-free Survival (PFS) [Up to 44 months]

   Time from initial treatment date of to date of documented progression of disease progression (TTP)

2. 1-year Overall Survival (OS) [Time from initial treatment date, up to 1 year]

   1-year survival is the estimated probability of surviving one year expressed as a percent (probability of survival is not probability of dying).

3. Median Overall Survival (Point Estimate) [Up to 44 months]

   Median overall survival is the (point) estimate of the time corresponding to 50% estimated probability of survival.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a written informed consent obtained prior to the initiation of study procedures.

• Male and female subjects greater than or equal to 18 years of age.

• Patients must have histologically confirmed recurrent stage III or stage IV melanoma (AJCC 6th edition classification). Cutaneous melanoma, ocular or mucosal melanoma will be eligible.

• Patients must have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Baseline measurements must be obtained within 4 weeks prior to initiating therapy.

• Patients must have adequate hematologic, renal, and liver function as evidenced by the following (within 4 weeks prior to starting the study drugs):

• WBC greater than or equal to 3,000/mm3

• Lymphocytes greater than or equal to 1,000/mm3

• Platelets greater than or equal to 100,000/mm3

• Serum Creatinine less than or equal to 1.5 x upper limit of normal (ULN)

• Serum Bilirubin less than or equal to 1.5 x ULN

• Serum AST/ALT less than or equal to 2.5 x ULN

• Serum LDH less than or equal to 2.0 x ULN

• APTT less than < 40 s

• Patients must have fully recovered from any effects of major surgery, and be free of significant detectable infection.

• Patients must not have received any chemotherapy, hormonal therapy, radiotherapy, or biological therapy within the preceding 4 weeks.

• Patients must not have previous therapy with Anti-CTLA4 monoclonal antibodies (including CP-675,206 and MDX-010). Previous therapy with Interferon-alfa 2b in the adjuvant or metastatic setting is allowed. Previous therapy with other biological agents (including vaccines and GM-CSF) is allowed.

• Patients must have ECOG performance status of 0 or 1.

• Patients must not have autoimmune disorders (except vitiligo). Patients with positive titers for autoimmune antibodies are allowed on the study in the absence of history of clinical manifestations of autoimmune disease.

• Patients must not have conditions of immunosuppression or chronic requirement for treatment with systemic steroids, including oral steroids, continuous use of topical steroid creams or ointments, or any inhaled steroid containing inhalers. Patients who discontinue use of these classes of medication for at least 2 weeks are eligible. Treatment with steroids or other immunosuppressant medications is allowed during the study if clinically required to treat side effects related to autoimmunity that may develop secondary to the study agents.

• Patients must be free of brain metastasis by contrast-enhanced CT/MRI scans within 4 weeks prior to starting the study drugs. If known to have prior brain metastases, must not have evidence of active brain disease on two successive MRI evaluations at least 3 months apart (one of which is £ 4 weeks prior to starting the study drugs).

• Female patients of child bearing potential must have a negative pregnancy test, and must not be breast feeding.

• Patients must agree to use effective contraception (both males and females).

Exclusion Criteria

• Serious illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, hypertension, cardiac ischemia, myocardial infarction, severe cardiac arrhythmia), bleeding disorders, autoimmune diseases, severe obstructive or restrictive pulmonary diseases, active systemic infections, and inflammatory bowel disorders.

• Treatment with mitomycin C or nitrosureas within six weeks prior to study entry.

• Any significant psychiatric disease, medical intervention, or other condition, which in the opinion of the principal investigator, could prevent adequate informed consent or compromise participation in the clinical trial.

• Active infection or antibiotics within one-week prior to study, including unexplained fever (temp > 38.1°C).

• Treatment with anticoagulants, except to keep an indwelling line patent.

• Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the study.

• Treatment with any investigational product within 28 days of registration.

• History of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), celiac disease, or other chronic gastrointestinal conditions associated with diarrhea, or current acute colitis of any origin, or any history of diverticulitis (even a single episode) or evidence of diverticulitis at baseline, including evidence limited to CT-scan only.

• Patients who did not tolerate high-dose interferon-α therapy in the adjuvant setting will be excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UPCI Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• Ahmad Tarhini
• Pfizer

Investigators

• Principal Investigator: Ahmad Tarhini, MD, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ahmad Tarhini, Assistant Professor of Medicine, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT00610857
• Other Study ID Numbers: 05-125
• First Posted: Feb 8, 2008
• Last Update Posted: Jun 22, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Melanoma; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Interferon Alfa-2b + Tremelimumab
Arm/Group Description	Patients with stage IV melanoma (cutaneous, uveal, or mucosal) and measurable disease, most who had previously received therapy
Period Title: Overall Study
STARTED	37
COMPLETED	35
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Interferon Alfa-2b + Tremelimumab
Arm/Group Description	Patients treated with Tremelimumab 15 mg/kg at start of C1 + IFN-2b IV 20 MU/m2/d for 5 d/wk for 4 weeks; C2 onward- IFN-2b SQ 10MU/m2/d for 3 d/wk for 4 weeks
Overall Participants	37
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	14 37.8%
Male	23 62.2%

Outcome Measures

1. Primary Outcome

Title	Best Objective Response Rate (BORR)
Description	Intention to treat response rate is estimated by the proportion of patients with a best response of CR, PR, or SD by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.0
Time Frame	Up to 44 months

Outcome Measure Data

Analysis Population Description

Patients treated with Tremelimumab 15 mg/kg at start of C1 + IFN-2b IV 20 MU/m2/d for 5 d/wk for 4 weeks; C2 onward- IFN-2b SQ 10MU/m2/d for 3 d/wk for 4 weeks

Arm/Group Title	Interferon Alfa-2b + Tremelimumab
Arm/Group Description	Patients treated withTremelimumab 15 mg/kg at start of C1 + IFN-2b IV 20 MU/m2/d for 5 d/wk for 4 weeks; C2 onward- IFN-2b SQ 10MU/m2/d for 3 d/wk for 4 weeks
Measure Participants	37
Number (90% Confidence Interval) [percentage of patients]	24

2. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Time from initial treatment date of to date of documented progression of disease progression (TTP)
Time Frame	Up to 44 months

Outcome Measure Data

Analysis Population Description

Patients with stage IV melanoma (cutaneous, uveal, or mucosal) and measurable disease, most who had previously received therapy

Arm/Group Title	Interferon Alfa-2b + Tremelimumab
Arm/Group Description	Patients treated withTremelimumab 15 mg/kg at start of C1 + IFN-2b IV 20 MU/m2/d for 5 d/wk for 4 weeks; C2 onward- IFN-2b SQ 10MU/m2/d for 3 d/wk for 4 weeks
Measure Participants	37
Median (95% Confidence Interval) [months]	6.4

3. Secondary Outcome

Title	1-year Overall Survival (OS)
Description	1-year survival is the estimated probability of surviving one year expressed as a percent (probability of survival is not probability of dying).
Time Frame	Time from initial treatment date, up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Interferon Alfa-2b + Tremelimumab
Arm/Group Description	Patients treated withTremelimumab 15 mg/kg at start of C1 + IFN-2b IV 20 MU/m2/d for 5 d/wk for 4 weeks; C2 onward- IFN-2b SQ 10MU/m2/d for 3 d/wk for 4 weeks
Measure Participants	37
Number (95% Confidence Interval) [percentage of patients]	62

4. Secondary Outcome

Title	Median Overall Survival (Point Estimate)
Description	Median overall survival is the (point) estimate of the time corresponding to 50% estimated probability of survival.
Time Frame	Up to 44 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Interferon Alfa-2b + Tremelimumab
Arm/Group Description	Patients treated withTremelimumab 15 mg/kg at start of C1 + IFN-2b IV 20 MU/m2/d for 5 d/wk for 4 weeks; C2 onward- IFN-2b SQ 10MU/m2/d for 3 d/wk for 4 weeks
Measure Participants	37
Median (95% Confidence Interval) [months]	21

Adverse Events

Time Frame	5 years.
Adverse Event Reporting Description	Includes adverse events that were considered either study treatment-related or unrelated.
Arm/Group Title	Interferon Alfa-2b + Tremelimumab (Related and Unrelated AEs)
Arm/Group Description	Patients treated withTremelimumab 15 mg/kg at start of C1 + IFN-2b IV 20 MU/m2/d for 5 d/wk for 4 weeks; C2 onward- IFN-2b SQ 10MU/m2/d for 3 d/wk for 4 weeks per cycle.
All Cause Mortality
	Interferon Alfa-2b + Tremelimumab (Related and Unrelated AEs)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Interferon Alfa-2b + Tremelimumab (Related and Unrelated AEs)
	Affected / at Risk (%)	# Events
Total	15/37 (40.5%)
Blood and lymphatic system disorders
Pain, Abdomen NOS	1/37 (2.7%)
Hemorrhage, CNS	1/37 (2.7%)
Cardiac disorders
Thyroid function, high (hyperthyroidism, thyrotoxicosis)	1/37 (2.7%)
Endocrine disorders
Renal failure	1/37 (2.7%)
Gastrointestinal disorders
Fatigue (asthenia, lethargy, malaise)	1/37 (2.7%)
Ulceration	1/37 (2.7%)
Thrombosis/thrombus/embolism	1/37 (2.7%)
Colitis	1/37 (2.7%)
General disorders
Neutrophils/granulocytes (ANC/AGC)	1/37 (2.7%)
Bronchospasm, wheezing	1/37 (2.7%)
Metabolism and nutrition disorders
Supraventricular and nodal arrhythmia, Atrial fibrillation	1/37 (2.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy - possibly related to cancer treatment	1/37 (2.7%)
Nervous system disorders
Diarrhea	1/37 (2.7%)
Renal and urinary disorders
Diarrhea	1/37 (2.7%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/37 (2.7%)
Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation)	1/37 (2.7%)
Skin and subcutaneous tissue disorders
Vomiting	1/37 (2.7%)
Vascular disorders
GGT (gamma-Glutamyl transpeptidase)	1/37 (2.7%)
Encephalopathy	1/37 (2.7%)
Other (Not Including Serious) Adverse Events
	Interferon Alfa-2b + Tremelimumab (Related and Unrelated AEs)
	Affected / at Risk (%)	# Events
Total	37/37 (100%)
Blood and lymphatic system disorders
Hemoglobin	10/37 (27%)
Leukocytes (total WBC)	13/37 (35.1%)
Neutrophils/granulocytes (ANC/AGC)	19/37 (51.4%)
Edema: limb	5/37 (13.5%)
Cardiac disorders
Hypertension	3/37 (8.1%)
Gastrointestinal disorders
Dehydration	3/37 (8.1%)
Gastrointestinal	3/37 (8.1%)
Mucositis/stomatitis (clinical exam), Oral cavity	7/37 (18.9%)
Constipation	13/37 (35.1%)
Taste alteration (dysgeusia)	17/37 (45.9%)
Vomiting	17/37 (45.9%)
Diarrhea	21/37 (56.8%)
Anorexia	25/37 (67.6%)
Nausea	29/37 (78.4%)
General disorders
Sweating (diaphoresis)	6/37 (16.2%)
Insomnia	9/37 (24.3%)
Weight loss	11/37 (29.7%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	27/37 (73%)
Rigors/chills	29/37 (78.4%)
Fatigue (asthenia, lethargy, malaise)	36/37 (97.3%)
Pain, Extremity-limb	6/37 (16.2%)
Pain - Other	7/37 (18.9%)
Pain, Back	8/37 (21.6%)
Pain, Abdomen NOS	10/37 (27%)
Pain, Head/headache	12/37 (32.4%)
Pain, Muscle	16/37 (43.2%)
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	4/37 (10.8%)
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils, Upper airway NOS	4/37 (10.8%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	6/37 (16.2%)
ALT, SGPT (serum glutamic pyruvic transaminase)	6/37 (16.2%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	8/37 (21.6%)
CPK (creatine phosphokinase)	9/37 (24.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal/Soft Tissue	4/37 (10.8%)
Nervous system disorders
Mood alteration, Agitation	3/37 (8.1%)
Neuropathy: motor	4/37 (10.8%)
Neuropathy: sensory	5/37 (13.5%)
Dizziness	6/37 (16.2%)
Mood alteration, Depression	7/37 (18.9%)
Neurology	8/37 (21.6%)
Mood alteration, Anxiety	12/37 (32.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	5/37 (13.5%)
Cough	12/37 (32.4%)
Skin and subcutaneous tissue disorders
Dermatology/Skin	4/37 (10.8%)
Dry skin	6/37 (16.2%)
Hair loss/alopecia (scalp or body)	6/37 (16.2%)
Pruritus/itching	23/37 (62.2%)
Rash/desquamation	26/37 (70.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.